S150: TIMING AND CLONAL TRAJECTORY TO CHRONIC MYELOID LEUKAEMIA DRIVEN BY THE PHILADELPHIA CHROMOSOME
Authors: Aleksandra Kamizela, Nicholas Williams, Joe Lee, Karim Mane, Kate Milne, Tony Green, Timothy Chevassut, Brian Huntly, E. Joanna Baxter, Jyoti Nangalia
Journal: HemaSphere (2023)

Topic: 7. Chronic myeloid leukemia - Biology & Translational Research Background: The discovery of the Philadelphia (Ph) chromosome in chronic myeloid leukaemia (CML) provided the very first recurrent genetic link to cancer and the hypothesis that this lesion provides an abnormal growth advantage to cells. Targeting BCR:ABL1 via tyrosine kinase inhibition (TKI) has since resulted in uniquely successful outcomes for the majority of CML patients, a result not replicated for other cancers. Aims: We aimed to investigate the hypothesis that CML may be characterised by a unique clonal trajectory and to determine the absolute timing and rate of BCR:ABL1 driven clonal expansion in patients. Methods: We studied 7 patients with chronic phase CML aged 22-61 at diagnosis. Blood and bone marrow samples were collected at diagnosis and in remission to grow single-cell derived colonies, capturing both BCR:ABL1-mutated and unmutated cells. Whole-genome sequencing (WGS) to a median depth of 13.1x was performed to identify somatic mutations in each of 583 colonies. We used these mutations to reconstruct phylogenetic trees of hematopoiesis and investigate clonal relationships between clades. We inferred the absolute timing of clonal expansion and estimated expansion rates using rtreefit and Phylofit, respectively. Mutational signatures and telomere lengths were analyzed with hdp and telomerecat in R. Results: Analysis of phylogenetic trees retraced the history of CML clones back to the earliest symmetrical divisions of the BCR:ABL1-mutated hematopoietic stem cell (HSC) and infer the pace of clonal expansion. In the 2 youngest patients in the cohort, diagnosed at ages 22 and 36, the time from the start of clonal expansion of the BCR:ABL1-mutated HSC to diagnosis was 3yrs (95% confidence interval (CI) 2.2-4.2yrs) and 3.9yrs (CI 3-5.3yrs) respectively. We observed a novel rapid pattern of branching suggestive of sustained explosive growth rates of 15,000%/yr (CI 1,300-86,000%/yr) and 23,000%/yr (CI 5,700-83,000%/yr), representing the highest inferred in vivo growth rates resulting from a single oncogene, and corresponding to the mutant clone doubling in size every 45-50 days. Three additional patients aged 45-55, also had short and rapid clonal trajectories from the start of BCR:ABL1-mutated clonal expansion to diagnosis, ranging from 4.9yrs (CI 3.8-6.6yrs) and an inferred growth rate of 16,000%/yr (CI 7,300-37,000%/yr) to 7.1yrs (CI 5.6-9.1yrs) with a growth rate of 1,800%/yr (CI 1,200-2,700%/yr). In 2 patients, aged 52 and 61, we observed longer clonal trajectories of 16.1yrs (CI 12.8-19.5yrs) and 13.7yrs (CI 11.8-15.8yrs) respectively. In the older patient, rate of clonal expansion varied with a mean growth rate of 83%/year (CI 67-100%/year). Intriguingly, in this individual, TKI therapy was associated with clearance of only more rapidly dividing BCR:ABL1 mutant cells. BCR:ABL1-mutated cells had a significantly increased contribution of SBS1 mutational signature and markedly shorter telomere lengths, reflecting their history of excessive cell divisions. Importantly, there was no evidence of BCR:ABL1 or therapy related mutagenicity. Summary/Conclusion: We retrace HSC histories of CML and identify the fastest oncogene driven clonal outgrowth rates reported to date. In many patients with CML, BCR:ABL1 transformation often occurs a few years before diagnosis and results in explosive clonal expansion. These data contrast with the early-in-life, slow, sequential clonal trajectory to Ph- myeloproliferative neoplasms, clonal haematopoiesis, and evolutionary trajectories in solid malignancies. Our data also raise the possibility that differential clonal trajectories within CML may be linked to subsequent therapeutic response. Keywords: Chronic myeloid leukemia, Clonal expansion